The long-term objective of these studies is to understand the Basic Underlying Mechanism of Musculoskeletal Aging (number 17). Beyond age 35 years the amplitude of pulsatile growth hormone (GH) release and IGF-1 decline markedly. These changes are accompanied by a decline in muscle strength, an increase in the ratio of fat/muscle, reduced tolerance for exercise and reduced bone mineral density. It is known that GH deficiency in young adults results in a similar phenotype. A new G-protein coupled receptor, the GH-Secretagogue Receptor (GHS-R), was characterized and cloned in 1996 and established as an important regulator of pulsatile GH release. When frail elderly musculoskeletaly impaired subjects are chronically treated with the synthetic GHS- R ligand, MK-0677, the age-related decline in activity of the GH/IGF-1 axis is reversed resulting in increased muscle mass, modest improvements in strength and increased bone turnover. The decline in strength observed in the control group over a 12-month period was arrested by MK-0677 treatment. Because chronic treatment with the synthetic ligand, MK-0677, restores the pulsatile profile of GH release and IGF-1 levels in 61-92 year old subjects to that of subjects in their twenties, we hypothesize that the production of a natural endogenous ligand for the GHS-R declines during aging. To test this hypothesis is the natural ligand must first be identified and then quantitated during aging. This proposal is designed to identify the endogenous natural ligand. A decline in production of this ligand may have profound consequences, not just on the GH/IGF-1 axis to affect muscle and bone mineral density, but at those centers of the brain where the GHS-R is expressed that control memory, learning, cognition, mood and quality of sleep. Specific Aim 1 makes use of phage display peptide libraries to allow enrichment and amplification of specific peptides that bind to the GHS-R. Knowledge of the peptide sequence will be used to search EST and genomic databases for GHS-R ligand candidates and to clone the gene. Specific Aim 2 is to compare the biological properties of this ligand with synthetic ligands and determine where it is expressed by in situ hybridization. This information will establish the foundation for defining the role of this endogenous ligand during muskuloskeletal aging.